Breast cancer is the most common type of non-cutaneous cancer among women in the United States and continues to provide a challenge regarding treatment due to the common development of resistance to therapy. In postmenopausal women, obesity has consistently been associated with higher breast cancer risk, caused in part by increased circulating estrogen levels. Aromatase inhibitors (Als) are a promising class of drug for postmenopausal breast cancer treatment that decreases estrogen synthesis. Among other factors, the activation of Akt/mTOR plays a critical role in resistance to therapy. Recent studies have demonstrated that endocrine therapy in parallel with mTOR inhibition using small molecule signal transduction inhibitors (STIs) can restore endocrine therapy responsiveness. The focus of the proposed studies is to determine the effect of obesity on mammary tumor responsiveness to the Al letrozole, either alone or in combination with an STI. Long-term goals of this proposal include determining the mechanism underlying endocrine therapy resistance in the context of obesity. The central hypothesis is that obesity contributes to endocrine therapy resistance for postmenopausal breast cancer through an Akt/mTOR- dependent mechanism. To accomplish the aims, we will use a postmenopausal mouse model of diet- induced obesity employing MMTV-Wnt-1 mammary tumor cells. The aims are to: (1) Characterize the impact of obesity on mammary tumor development and Akt/mTOR signaling, (2) Characterize the impact of obesity on STI effects on mammary tumor development and Akt/mTOR signaling, and (3) Determine the impact of obesity on mammary tumor response to aromatase inhibition alone or in combination with mTOR inhibition. Completion of the proposed studies will establish the molecular mechanism underlying the obesity modulation of postmenopausal breast cancer and lead to a greater understanding of the role obesity plays in response to endocrine therapy agents. Furthermore, the proposed studies will contribute to improving the quality and efficacy of endocrine therapy for obese postmenopausal breast cancer cases.